By Deborah Borfitz 

May 17, 2022 | The clinical research situation in Ukraine has changed from “peaceful, predictable, and promising” a year ago to “complex, complicated, and difficult” since the Feb. 24 Russian invasion, according to Serhiy Mykhaylov, Merck’s clinical research director in the country speaking during a recent DIA webinar on the ethical dilemmas the war has created for those supporting study participants in the region. Before the conflict, its 42 million population, abundance of well-educated physicians and experienced investigators, and well-established infrastructure for both healthcare and clinical trials made it an ideal location to place studies. 

In the 2020-2021 period, 200 new clinical trials were approved in Ukraine, Mykhaylov notes, and as of six months ago the country had 500 active ongoing studies. Merck alone was sponsoring more than 70 trials—some planned or in the initiation phase and others ongoing.  

But over the past few months, the situation has “changed completely,” he says. While Ukrainian citizens were uniformly shocked by the Russian attack, the immediate response of companies sponsoring clinical studies there was to halt enrollment of new patients, randomization into studies, and the initiation of new investigative sites.  

Guideposts for decision-making are available from the three main documents underpinning ethical research conduct, according to Lindsay McNair, M.D., chief medical officer at WCG (an independent institutional review board) and co-chair of the DIA Bioethics Community. These include the 10-point Nuremburg Code developed in response to World War II atrocities, the much-revised Declaration of Helsinki written by the World Medical Association to guide physicians, and the U.S.-specific Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research that covers respect for persons, justice, and beneficence (“seek to do good” principle) in six short pages.  

Lessons learned from the 2014 Crimea annexation, a more limited conflict with Russia in Eastern Ukraine, can also be applied when it comes to how patients, contract research organizations, and sponsors access sites, Mykhaylov says. The pandemic has additionally equipped companies to deal with disruptions to on-site study monitoring. 

Getting investigational products to their destination is another part of the story, he continues. By far the biggest impact of the war has been the risk to human life that caused more than 5.5 million citizens to flee the country. 

Geography also plays a role, with the ravages of war being felt predominantly in Eastern and Northern Ukraine hardest hit by the invasion, says Mykhaylov. But the effects are more far-reaching because of mass in-country migration since April. In the capital (Kyiv) and other major cities in north-central Ukraine, which were not as affected, it was more “life as normal” two months into the onslaught other than the military presence on the street. 

Conflicting Principles 

The “no patient left behind” attitude that Merck adopted during the pandemic has held steady during Russia’s war in Ukraine, but new ethical dilemmas have emerged with the man-made disaster, he continues. Among them are questions about whether to continue with a treatment or study and when oversight is sufficient to safeguard patient safety.  

Six weeks after the invasion, Merck resumed distribution of clinical supplies and investigational products to the country, but products were all being moved by land since the airspace over Ukraine was closed, says Mykhaylov. Less than 1% of trial participants transferred abroad, or about 10 out of roughly 1,000 enrollees in its studies. 

Two ethical principles could be in conflict here, McNair points out, referencing oversight to protect the safety of participants as well as the “ethical drive… to move science forward” by finishing a study. It’s more a practical issue when the infrastructure for oversight has been compromised, she adds. 

Given that Merck’s pipeline is 70% oncology studies, the balancing act is often between the benefits of treatment and the risks to life and data integrity, Mykhaylov says. “We need to ensure treatment continues if it’s safe,” which includes access to lab services for safety testing in advance of treatment and staying in close contact with investigators. Therapeutic studies for conditions that are not life-threatening have more protocol flexibility and can pause without any significant risk to safety or participants’ health condition. 

The oncology treatment trials are considered one by one with a host of factors—including the indication, stage, and progress on enrollment—influencing decisions about what is best for the study and for patients, says Mykhaylov. On the operational side, especially, Merck tracks the situation “site by site and patient by patient” and as necessary will transfer patients to a different investigator and provide some transportation support. 

Mobility Team 

Agata Bloswick, Ph.D., executive director, global head start-up operations at Labcorp Drug Development, next spoke about operational challenges she has faced professionally as chair of a mobility team handling relocations for sites as well as personally as a resident of Poland that has accepted millions of Ukrainian refugees. 

Surprisingly, she says, the industry overall—from small biotechs to large pharma—has not relocated many patients even though one-third of the entire population of Ukraine has been displaced either internally or abroad. “The numbers for trial participants are significantly lower,” she notes. That may be because they are in a safe location or the windows between study visits are relatively long (e.g., every six months), although the trend could change as the conflict continues. 

Patients who have been internally displaced are not as logistically challenging to relocate, says Bloswick, since they speak the same language, have the same insurance, and signed the same informed consent documents. With international displacements, investigators provide guidance on whether a participant can safely continue with a study and if they need remote support. 

All sorts of questions tend to emerge regarding regulations in the new country, if the study has been approved there, and whether participants have access to transportation or if they want to drop out of the trial because it has fallen off their priority list or they are no longer physically able to participate. “These are daily challenges of the patient mobility group, [as Mykhaylov says] site to site and patient to patient,” Bloswick shares.  

Realizing “ad hoc triage” of study participants was needed, Labcorp purpose-built the mobility team by bringing together experts in regulatory affairs, ethics, quality, clinical operations, and decentralized clinical trials, together with a delivery team. The group meets regularly to produce relocation guidance, including differences that will be encountered country to country and any learnings from COVID that might be applicable.  

Changing Vulnerability 

The war’s personal impact on Bloswick stemmed from the fact that she provided temporary shelter to the extended family of a Ukrainian colleague, including multiple children. They stayed with Bloswick for a month while they secured housing and got the kids enrolled in school.  

One person in the displaced group happened to be a clinical trial participant and became a “firsthand mobility case.” As Bloswick recounts, she didn’t know who to call since the original investigator was back in Kyiv. But she was eventually able to identify the trial by the protocol number and find a clinical research associate in Poland for that study. 

When most Ukrainian participants started in their trial, they were not considered part of a “vulnerable population,” Bloswick continues. But they had to be classified as such with the onset of the war, whether they were internally or externally displaced. New questions arose, such as whether they would have access to healthcare, or a needed treatment, outside of the study. If that was their only reason to continue participating, it was not the right one, she adds. 

The intake principal investigator might have to accept relocated study participants without knowledge of their medical history, at least if source documents could not be obtained from the original site, putting those individuals in a difficult situation, says Bloswick. A balance also has to be struck between lessening the bureaucratic hassle of multiple rounds of informed consent and ensuring participants make an educated decision, and one answer may be to get consent verbally prior to their relocation and confirm it once they arrive.    

Some sponsors were “really nervous” about the relocation process until it was explained to them how everything would be documented and who would be consulted along the way. It was not always entirely clearly how to proceed, since not all countries have issued ethics guidance, she says. 

The mobility team could draw in part from 2014 decisions about how much to share in advance that might incentivize individuals to continue with a trial that may no longer be in their best interest due to dangers on the ground, says Bloswick. Among a group of about a dozen patients directed to new sites in Ukraine without any sort of relocation assistance, eight opted to make the move. One investigator who was “on the fence” about continued participation in a trial also decided to do so after receiving a relocated participant. “We need to learn to triage patients to the right options,” she concludes. 

Question Of Housing 

Trial participants need to sign a new consent document with a site-to-site transfer, Mykhaylov clarifies during the post-presentation Q&A. “In terms of the impact on vulnerability, in most cases we are not talking about enrolling a new patient but [consenting] to continue study participation [at a new location].” 

Consent is an “ongoing process… affirming [participants’] continuous consent,” interjects McNair. Some organizations have talked about providing substantial support to displaced individuals—including an apartment for the duration of their study—and while this sounds generous from a humanitarian perspective she wonders if it might become “undue inducement” for them to remain in a trial.  

“Reality works differently,” Mykhaylov responds, noting limitations and restrictions in corporate standard operating procedures. “The majority of the time, the amount of monetary funds and reimbursement for participants in a trial is limited and fixed” at a level unlikely to influence the desire to participate. When study sponsors transfer patients to a new site, they may not even be providing transportation let alone housing once they get there.